The serotonin neurotransmitter system and one of its key components, the serotonin transporter (SERT), is the primary target of this project. The development of the SERT knockout mouse in the LCS provided a new living tool to study SERT and serotonin receptors, the target molecules for the largest numbers of neuropsychiatric drugs used in the world. 30 plus neurochemical, behavioral and other phenotypic changes have been discovered in the serotonin knockout mouse. The resulting data is helping to guide the LCS and other laboratories in investigations of the multiple variants recently discovered in the human SERT gene. The broad goal of our studies is a better understanding of the serotonin neurotransmitter system and its contributions to physiology, behavior and human disorders, especially neuropsychiatric disorders. Serotonin has been implicated in almost every physiological function known. The serotonin transporter (SERT) recycles seorotonin after its release, thereby terminating the action of seotonin at its receptors. In our attempt to better understand serotonin's function, we have generated a mouse model which either lacks the serotonin transporter or has a 50% reduction in serotonin transporter expression. The SERT -/- and +/- mice have gene-proportionate increases in the extracellular fluid serotonin )5-HT) concentrations. i.e., 9- and 5-fold excesses respectively over +/+ mice, with the SERT deficiency present since conception. Our mouse model provides us with a living genetic tool to explore just what 5-HT does in normal physiology and in disease. This mouse model is providing an experimental window not previously available to test hypotheses about 5-HT's contributions to multiple biological processes and human diseases. Our mouse model also provides an opportunity to further elucidate physiological control mechanisms, neuroanatomical development. emotional states, and drug effects. A reduction of aggression and of behavioral despair and increase in anxiety-like behaviors in the SERT knockout mice reported in the last year may be a result of increased availability of serotonin in the extracellular space. Another consequence of this excess serotonin is a decrease in 5-HT1A expression and function in 5-HTT knockout mice. furthermore, we reported this past year that these mice also show altered expression of 5-HT2A/C receptors in a regionally specific manner. 5-HT2A/C receptors are increased in the amygdala, a brain region associated with aggression. The role of serotonin and its pre- and post- synaptic receptors along with associated intracellular signally pathways may underly the expression of anxiety and depression. In addition, as serotonin has a trophic effect on neuronal cells, we are investigating the role of the serotonin transporter and certain neurotrophic factors such as BDNF in neuronal function, survival, and development. We have successfully developed a mouse SERT x BDNF double knockout mouse model to further investigate the role of the serotonin transporter and BDNF in the developing nervouse system as human genetic studies have separately implicated both genes in the development of affective disorders.